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Determination of protein–ligand binding modes using fast multi-dimensional NMR with hyperpolarization

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Abstract

Elucidation of small molecule–protein interactions provides essential information for understanding biological processes such as cellular signaling, as well as for rational drug development. Here, multi-dimensional NMR with sensitivity enhancement by dissolution dynamic nuclear polarization (D-DNP) is shown to allow the determination of the binding epitope of folic acid when complexed with the target dihydrofolate reductase. Protein signals are selectively enhanced by polarization transfer from the hyperpolarized ligand. A pseudo three-dimensional data acquisition with ligand-side Hadamard encoding results in protein-side [13C, 1H] chemical shift correlations that contain intermolecular nuclear Overhauser effect (NOE) information. A scoring function based on this data is used to select pre-docked ligand poses. The top five poses are within 0.76 Å root-mean-square deviation from a reference structure for the encoded five protons, showing improvements compared with the poses selected by an energy-based scoring function without experimental inputs. The sensitivity enhancement provided by the D-DNP combined with multi-dimensional NMR increases the speed and potentially the selectivity of structure elucidation of ligand binding epitopes.

Graphical abstract: Determination of protein–ligand binding modes using fast multi-dimensional NMR with hyperpolarization

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Supplementary files

Article information


Submitted
15 Jan 2020
Accepted
05 May 2020
First published
06 May 2020

This article is Open Access
All publication charges for this article have been paid for by the Royal Society of Chemistry

Chem. Sci., 2020, Advance Article
Article type
Edge Article

Determination of protein–ligand binding modes using fast multi-dimensional NMR with hyperpolarization

Y. Wang, J. Kim and C. Hilty, Chem. Sci., 2020, Advance Article , DOI: 10.1039/D0SC00266F

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